Method and compositions for reducing dysfunction in angioplasty procedures

ABSTRACT

A method for reducing dysfunction in angioplasty procedures and particularly, in myocardial angioplasty procedures in human beings is desired. The method involves the introduction of a selected amount of intra-arterial prostaglandin compound into an artery, such as a coronary artery, in which an angioplasty procedure is to occur. The prostaglandin compound will provide cyto-protection and provide antithrombotic effects and antiplatelet effects and antispasmatic effects. The prostaglandin compound is administered in a pharmacological amount, that is, an amount substantially greater than the prostaglandin which would be generated by a normal myocardial artery when insulated and thus, constitutes an administration substantially greater than an amount which would be administered in a replacement therapy. A composition is also provided for reducing dysfunction in angioplasty procedures and comprises a selected amount of a carrier and a prostaglandin compound carried in a specified amount and which carrier does not alter the prostaglandin compound and releases the prostaglandin compound at a rate sufficient to dilate blood vessels to thereby produce the required efficacy. A prepackaged combination of components provides for the complete administration of the prostaglandin compound before, during and after the angioplasty procedure.

RELATED APPLICATION

This application is a continuation-in-part of our patent applicationSer. No. 784,160, filed Oct. 4, 1985, now abandoned, entitled METHOD FORREDUCING DYSFUNCTION IN ANGIOPLASTY PROCEDURES.

BACKGROUND OF THE INVENTION 1. Field of the Invention

This invention relates in general to certain new and useful improvementsin methods for reducing dysfunction in angioplasty procedures, and moreparticularly, to a method of the type stated which relies upon theintroduction of a selected amount of a prostaglandin compound into theartery in which an angioplasty procedure is performed and compositionscontaining specified amounts of the prostaglandin compound to produce ahigh degree of efficacy. 2. Brief Description of the Prior Art

Angioplasty procedures were first used in the 1960's and since that timehave gained widespread acceptance as a means of obtaining dilation ofarteries. Particularly, angiomyocardial angioplasty procedures havebecome widely adopted to obtain dilation of myocardial arteries.

In the conventional angioplasty procedure, a small balloon tippedcatheter is introduced into an artery, often using a guide wire or acatheter tube in which a balloon may be positioned at an arterystenosis. These balloons and catheter assemblies are often referred toas coronary balloon dilation catheters. In many cases, the catheters aredesigned to permit continued distal dye injections through the balloonto permit visual verification of proper approach to a lesion or otherarea in which the procedure is to be employed.

It is well known that cardiac angioplasty procedures involve a risk ofboth local and systemic thromboembolic effects, which are even greaterthan cardiac catheterization. Usually, the patient is injected withheparin and various known blockers during the procedure. Moreover, for asubstantial period of time after the procedure, which may be six monthsto a year, or longer, the patient must necessarily be treated withplatlet inhibiting drugs. Other complications which often occur duringtransluminal angioplasty procedures include disection of an artery suchas a coronary artery, intramural hematoma, and occlusion of the arteryresulting in myocardial infarction.

Some of the problems which appear to arise after angioplasty proceduresinclude early restenosis and possibly abrupt occlusion. It is thereforenecessary to provide some means which exhibits a cytoprotective effectduring ischemia and which may salavage the myocardium duringtransluminal angioplasty, particularly when high inflation pressures areneeded for a long duration, as for example, up to six minutes, orotherwise, in the case of an unstable angina.

In order to overcome some of the dysfunction resulting from percutaneoustransluminal coronary angioplasty, heparin and intracoronarynitroglycerine, as well as systemic calcium blockers have been used. Inaddition, various preparations have been employed prior to theangioplasty procedures and include, for example, aspirin, Persantine,intravenous dextran, etc. Nevertheless, the various complications stillpersist. Moreover, these complications account for virtually all of theproblems in percutaneous transluminal coronary angioplasty. In the NHLBIregistry, as reported by Cowley et al in the American Journal ofCardiology, 1984, the results of the cases of 3,079 patients wereexamined and 418 patients suffered some form of post angioplastyprocedure complications.

There have been numerous publications dealing with the various types ofprostaglandin compounds and their effectiveness for providingantiplatelet effects and antithrombotic effects and antispasmic effects.For example, U.S. Pat. No. 4,239,778 to Venton et al, discloses a novelazaprostanoic acid analog and its effectiveness as an inhibitor ofplatelet aggregation. U.S. Pat. No. 4,095,036 to Yankee discloses an8-beta 12-alpha PG-2 prostaglandin type analog and its effectiveness incontrolling spasm, particuarly in asthmatic conditions, as well as adecrease in blood platelet adhesiveness. This patent also discloses theuse of various prostaglandin analogs as being effective to prevent theformation of thrombi to thereby prevent post operative thrombosis andtheir effectiveness in and prevention of myocardial infarcts.

In like manner, U.S. Pat. No. 4,205,178 to Axon discloses variousprostaglandin E derivatives and analog compounds which are alsoeffective in prevention of myocardial infarcts and effective ininhibiting platelet aggregation. This patent also discloses the use ofthese compounds as hypotensive agents when administered at a rate ofabout 0.01 to about 50 micrograms per kilogram of body weight perminute.

There have been several articles dealing with the effects ofprostaglandin reduction as a result of arterial insult. For example, thearticle entitled "Vessel Wall Arachidonate Metabolism After Angioplasty"by Andrew Cragg, M.D. et al discusses the mechanism of post angioplastyvasospasm and the postulation that a reduction in prostaglandin I-2 orprostaglandin E-2 might contribute to spasm of a dilated artery, asreported in the May 1, 1983 edition of the American Journal ofCardiology, Volume 51, pages 1441 et seq. In like manner, a discussionof paralysis and hyperemia of an arterial wall and altered vasomotortone has been demonstrated following percutaneous transluminalangioplasty and the effect of reduction of prostaglandin compoundsgenerated by the body, in "Prostaglandins and Angioplasty" as reportedin Interventional Radiology, Dec. 1983, page 681 et seq.

OBJECTS OF THE INVENTION

It is, therefore, a primary object of the present invention to reducedysfuction in an angioplasty procedure, by administering to a patient, apharmacological amount of a composition which will provide antiplateleteffects, antispasmatic effects and probable antithrombotic effects.

It is another object of the present invention to reduce the problemswhich frequently arise during percutaneous transluminal coronaryangioplasty by adminstering to the patient a pharmacological amount of aprostaglandin composition.

It is a further object of the present invention to reduce thedysfunction which can arise in or from an angioplasty procedure byadministering to a patient a prostaglandin E-1 composition, both duringthe angioplasty procedure and intravenously for a selected time periodthereafter.

It is another salient object of the present invention to provide amethod of reducing dysfunction which may arise in an angioplastyprocedure by adminstering to an intracoronary artery of the patient, anamount of a prostaglandin compound substantially in excess of the amountwhich would have been generated by a normal myocardial artery wheninsulted, such that the amount of prostaglandin compound administered issubstantially greater than an amount which would be administered in areplacement therapy.

It is also an object of the present invention to provide a compositionfor reducing the dysfunction which can normally arise in an angioplastyprocedure and which comprises a selected carrier containing a specifiedamount of a prostaglandin compound to produce the desired efficacy.

It is still another object to provide a pre-packaged combination ofcomponents which is effective for reducing dysfunction in an angioplastyprocedure.

With the above and other objects in view, our invention resides in thenovel method employed in using a prostaglandin composition to reduce theeffects of dysfunction in angioplasty procedures and the prostaglandincompositions which are effective for this purpose.

BRIEF SUMMARY OF THE DISCLOSURE

The present invention relies on a discovery that it is possible tosubstantially reduce dysfunction in angioplasty procedures in humanbeings, by introduction in relation to an artery in which an angioplastyprocedure is to occur, a selected amount of intra-arterial prostaglandincompound. This prostaglandin compound is administered in a proper amountwhich will provide cyto-protection and provide antithrombotic effects,antiplatelet effects and antispasmic effects.

The prostaglandin compound may adopt the form of several well knownprostaglandin analogs and isomers, as hereinafter described, andinclude, for example, the prostaglandin E compounds, the prostaglandin Icompounds, the prostaglandin D compounds, the prostaglandin F compounds,Ciprostene, etc. Some of the more preferred prostaglandin compounds usedin accordance with the present invention include, prostaglandin E-1,prostaglandin I-2 and Ciprostene.

The prostaglandin compound may be administered before the angioplastyprocedure and generally during the angioplasty procedure and in manycases, it is administered for a selected time period thereafter. In thecase of a coronary angioplasty procedure, an intracoronary bolusinjection is administered, followed by a continuous intravenousinjection for a selected time period, as for example, 6 to 12 hours ormore. More preferably, an intracoronary prostaglandin bolus injection isadministered immediately prior to the procedure and anotherintracoronary prostaglandin bolus injection is administered immediatelyafter the procedure, and which is followed by the intravenousadministration. Intracoronary prostaglandin administration during theprocedure may also take place, as required.

The prostaglandin compound may be dissolved in a liquid carrier, as forexample, a dehydrated alcohol. However, other liquid carriers, hereafterspecified may be used. The liquid carrier must be pharmaceuticallyacceptable and pharmacologically inactive.

It is well known that the normal body artery will generate one or moreof the selected prostaglandin compounds, as for example, prostaglandinI-2 when the artery is insulted, that is stressed or otherwise subjectedto an injury. See for example, "Vessel Wall Archiondonate MetabolismAfter Angioplasty" by Andrew Cragg, M.D. et al, supra. See also, "TheTreatment of Vasospastic Disease With Prostaglandin E-1", BritishMedical Journal, Volume 201. In a typical myocardial insult, themyocardial artery will generate prostaglandin usually in an amount ofabout one picogram up to a maximum of about three picograms. See forexample, "Vascular Prostaglandin and Thromboxane Production in a CanineModel of Myocardial Ischemia" by James M. Schmitz et al, CirculationResearch, Volume 57, No. 2, Aug. 1985; "Prostaglandins in CardiovascularMedicine: Part 1", by John G. Harold, M.D., William E. Shell, M.D. etal; "Cardiovascular Reviews and Reports", Volume 5, No. 9, Sept. 1984.

The amount of prostaglandin compound which is administered in accordancewith the present invention will range, depending on the condition of thepatient, including his or her health, age, previous coronary history,ability to accept the prostaglandin without adverse side effects andlike factors. Generally, in a coronary angioplasty procedure the amountof intracoronary prostaglandin administered to a patient ranges fromabout 25 nanograms to about 400 nanograms in bolus administrations andpreferably ranges from about 80 nanograms to about 260 nanograms, basedon prostaglandin E-1. The amounts of intracoronary prostaglandin whichare administered represent generally the total amount immediately priorto, during and immediately after the angioplasty procedure. Thus, thefirst bolus injection may comprise about 12 to about 200 nanograms, andpreferably about 40 to about 130 nanograms. The second or post-procedurebolus injection may also comprise about 12 to about 200 nanograms andpreferably about 40 to about 130 nanograms.

More preferably, about 65 nanograms of prostaglandin is administeredimmediately prior to the angioplasty procedure and an additional amountof about 65 nanograms of prostaglandin is administered immediately afterthe angioplasty procedure in bolus injections, based on prostaglandinE-1. If the prostaglandin compound is administered during theangioplasty procedure, the amounts administered immediately prior toand/or immediately after the procedure can be altered so that the totalamount administered falls within the above specified ranges.

The above ranges and specific amounts identified are those specificallyfor prostaglandin E-1. The ranges for the other prostaglandin analogsand isomers encompassed by the present invention and the specificamounts therefore are based on the efficacy of such isomers or analogscompared to prostaglandin E-1. Thus, for example, if a particularprostaglandin compound encompassed by the present invention has anefficacy of about 50 per-cent of that of prostaglandin E-1, the rangesand the specific amounts administered of that compound would be doubled.

Inasmuch as the prostaglandin compounds are adminstered in accordancewith the present invention in nanogram amounts (1-billionth of a gram)and at minimum, 25 nanograms, and the amount of prostaglandin which maybe generated by any body artery on insult is no greater than picogramamounts (1 trillionth of a gram) and usually less than 3 picograms, itcan be seen that the prostaglandin compounds administered in accordancewith the present invention are administered in amounts almost onethousand times, and usually much greater than one thousand times theamount of prostaglandin which could be generated by any normal bodyartery when insulted. Thus, the administration of prostaglandincompounds in the nanogram range as specified herein constitutes apharmacological amount and does not merely operate as a replacement, asfor example, in replacement therapy, that is, adminstration of an amountto replace that which may have been lost. As an example, cortisone maybe adminstered when body cortisone generation is depleted, although inamounts massively greater than the amounts depleted and is thusconsidered to be a pharmacological administration.

In view of the above explanation of administered prostaglandin amounts,the term "pharmacological amount" is used herein to mean theadministration of the prostaglandin compound in an amount substantiallygreater than the amount of prostaglandin which would be generated by amyocardial artery when insulted, and usually in an amount of about atleast one thousand times greater than the amount which would begenerated by a normal myocardial artery when insulted.

The administration of the prostaglandin compound in the pharmacologicalamount produces unexpected results in that the coronary artery or otherartery in which the prostaglandin was administered remains dilated for aperiod of two to three times longer than if nitroglycerine or verapamilor both were adminstered. Moreover, the amount of arterial dilation issubstantially greater and in many cases, the duct of the artery willremain dilated to twice its original size. As an example, in anangioplasty procedure, the artery may remain dilated for a period ofabout 45 seconds after removal of the catheter tip. With administrationof nitroglycerine, the artery may remain dilated for a period of abouttwo minutes. With the administration of prostaglandin E-1, the sameartery will remain dilated for a period of seven minutes or longer. Thisdilation period enables the body to overcome the results of abruptocculsion or other dysfunction which often results after an angioplastyprocedure. In addition, there is a substantially greater length of themyocardial artery which is dilated after the adminstration of theprostaglandin compound in the pharmacological amount. For example, alength of artery which is dilated may easily exceed two to three timesthe length of artery section which is dilated under the administrationof nitroglycerine.

This inventive process has many other advantages and has other purposeswhich may be made more clearly apparent from a consideration of theforms in which it may be embodied. These forms are set forth in thefollowing detailed description. However, its to be understood that thedetailed description is only for purposes of illustrating the generalprinciples of the invention and that it is to be understood that suchdetailed description is not to be taken in a limiting sense.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

In accordance with the present invention, a prostaglandin compound, ashereinafter described in more detail, is administered to the artery of ahuman being in which an angioplasty procedure is to occur. As indicatedpreviously, this prostaglandin compound is administered in an amountrequired to provide cyto-protection, antithrombotic effects,antiplatelet effects and antispasmic effects.

Generally, the prostaglandin compound is administered in the region inwhich the balloon catheter is to be inserted in order to reduce theotherwise adverse side affects and dysfunctions which may result whenattempting to dilate an artery. While the prostaglandin compound isgenerally administered just prior to the angioplasty procedure, in manycases it is desirable to administer the prostaglandin compound to thepatient during the procedure and/or for some time period thereafter andwhich is hereinafter described in more detail.

The method of the present invention was developed and has been proven tobe highly effective in myocardial angioplasty procedures. However, themethod of the present invention utilizing the administration of theprostaglandin compound is also highly effective for conductingangioplasty procedures in other portions of the human body. Thus, andwhile the preferred embodiment of the invention deals with myocardialangioplasty procedures, it is to be understood that the invention isapplicable to other angioplasty procedures as well.

Prostaglandin compounds which are used in accordance with the presentinvention are unsaturated fatty acids containing 20 carbon atoms andwhich usually include a pair of spaced apart side chains and each ofwhich form somewhat of a saw-tooth configuration, much in the same formas a hair pin. The two side chains are joined at one end only, by meansof a cyclopentane ring. At the other end, one of the side chainsterminates in a carboxylic acid group. In addition, the two side chainsmay be provided with one or more hydroxyl groups and/or ketone groupsalong the length thereof. These prostaglandins generally have a chemicalstructure which may be diagramatically illustrated in the followinggeneralized structural formula: ##STR1##

These prostaglandins, which are collectively often referred to as"eicosanoids", are known to exhibit biological activitities. Theseactivities include effects on the muscles or vessels, and/or inflamatoryresponse, thermo-regulation, platelet aggregation and the like. However,heretofore, it has not been recognized that the prostaglandin compoundcould be effective in reducing and even overcoming most of thedysfunction resulting from and in angioplasty procedures.

Prostaglandin E-1 is one of the preferred prostaglandin compounds whichmay be used in accordance with the method of the present invention. Theprostaglandin E-1 compound is metabolically derived from thepolyunsaturated fatty acid, dihomo-y-linolenic acid. This protaglandinE-1, has the empirical formula C₂₀ H₃₄ O₅ and this prostaglandin E-1compound has the chemical formula(11a,13E,15S)-11,15-dihydroxy-9-oxoprost-13-en-1-oic acid. Prostaglandincompounds of this type are more fully described in U.S. Pat. No.3,069,322 to Bergstromet al.

Prostaglandin E-1 can be structurally diagramed as follows: ##STR2## Thedotted lines between carbon No. 7 and carbon No. 8 indicate orientationof the atom and any group attached thereto below the plane of the ringin the alpha stereochemistry. In other words, that orientation is belowthe plane of this paper. The same holds true with the hydroxyl groups atthe No. 11 and No. 15 carbon atoms.

The prostaglandin used in accordance with the present invention is notlimited to the prostaglandin E-1 compound but encompasses otherderivatives of prostanoic acid and includes all other prostaglandinswhich provide the desired pharmacological effects such as cytoprotection. Those prostaglandins include, for example, prostaglandin E-2and prostaglandin E-3. The prostaglandin compounds are also deemed toinclude their lower alkyl esters and salts and amides which exhibit thedesired pharmacological activity. The prostaglandin E-2 compounds aredisclosed in U.S. Pat. No. 3,598,858 and esters thereof are disclosed inU.S. Pat. No. 3,691,216 and U.S. Pat. No. 3,795,697.

The numerals following the designations "prostaglandin" or"prostaglandin E" e.g. "1", "2", "3", represent the total number ofdouble bonds in the two side chains. Thus, prostaglandin E-2 has anadditional double bond between carbon No. 5 and carbon No. 6 and has astructural formula as follows: ##STR3## Prostaglandin E-3 has still anadditional double bond between carbon No. 16 and carbon No. 17 and has astructural formula as follows: ##STR4##

The compositions used in the method of the present invention alsoinclude the various isomers, as aforesaid, and include for exampleprostaglandin A isomers and the prostaglandin B isomers. Theprostaglandin A compounds do not include the hydroxyl group at carbonNo. 11, but have a double bond within the ring between carbon No. 10 andcarbon No. 11. Thus, prostaglandin A-1 has a structural formula asfollows: ##STR5##

The prostaglandin B compounds are isomers of the prostaglandin Acompounds having a double bond between carbon No. 8 and carbon No. 12.Thus, prostaglandin B-1 has a structural formula as follows: ##STR6##

The compound prostaglandin F is also, for example, encompassed by thepresent invention. The prostaglandin F compounds have a hydroxyl groupat the No. 9 carbon atom in place of a ketone group. Thus, prostaglandinF-2a has a structural formula as follows: ##STR7##

Those prostaglandin compounds having the chemical name "Ciprostene",namely, 9-methylcarbacyclin-calcuim salt and having the empiricalformula C₂₀ H₃₄ O₅ are also prostaglandin compounds which areencompassed by and achieve the efficacious results in accordance withthe present invention. The Ciprostene form of prostaglandin is usuallycharacterized as a calcuim salt and is a chemically stable analog ofprostacyclin. Ciprostene has a structural formula as follows: ##STR8##

It can be observed that the above are a non-limiting list of theprostaglandins which can be used and show that essentially anyprostaglandin which provides the desired pharmacological effect can beemployed. Moreover, in a broad sense and considering the generalizedstructural formula set forth above, it should be understood that theorientation, as shown in dotted lines, may be in or out of the plane ofthe cyclopentane, that is in or out of the plane of this paper.

Thus, the prostaglandin compound encompassed by the present invention,as represented by the generalized formula set forth above, is comprisedof a cyclopentane ring having a pair of side chains therein and one ofwhich terminates with a COO-- moiety. The "dotted" bond in thegeneralized structural formula may be in or out of the plane of thecyclopentane ring and any of the bonds in the side chains may be singlebonded or double bonded and which may also be in or out of the plane ofthe side chains and which side chains may include hydroxyl and ketonemoieties thereon which may be in or out of the plane of the cyclopentanering.

The COO-- group, which may be represented by COOR, is preferably acarboxylic acid group, e.g. COOH. However, the R may be hydrogen, asaforesaid, C₁ -C₁₂ alkyl or C₁ -C₁₀ cycloalkyl, C₆ -C₁₆ aralkyl, phenyloptionally substituted with one, two or three chloro or C₁ -C₃ alkyl. Ingeneral any parmacologically acceptable cation may be used.

The biosynthesis of prostaglandin compounds and their pharmacologicalactions are technically complex and the details of the synthesis are notnecessary for the practice of the present invention. However, in generalterms, the immediate fatty acid precursers of prostaglandin biosynthesisare dihomo-y-linoleic acid (chemically known as 5, 8, 11-eicosatrienoiccacid) and arachidonic acid (chemically known as 5, 8, 11,14-eicosatetraenoic acid). Substantial quanities of these acids, whichare primarily of dietary origin, may be synthesized in mammals fromlinoleic acid. The fatty acids are then stored as phospholipids. Thesephospholipids are then acted upon and released by the action of aphospholipase which is then the first step, and also rate limiting step,in the prostaglandin synthesis. The dihomo-y-linoleic acid is acted onby cyclooxygenase and this gives rise to prostaglandin E-1 through theendoperoxides PGG-1 and PGH-1.

Any carrier which is pharmaceutically acceptable and ispharmacologically inactive may be used to deliver the prostaglandincompound. Generally, dehydrated alcohols such as ethyl alcohol, normalpropyl alcohol, isopropyl alcohol, etc. may be employed. Other carrierswhich may be employed are for example saline solutions. The amount ofcarrier used to deliver a given amount of prostaglandin is determined bythe duration of the prostaglandin administration. Thus, if it is desiredto administer the prostaglandin over a nine hour period, a determinationof the amount of prostaglandin is made taking into consideration thepatients weight, as hereinafter described. The amount of carrierselected will be sufficient to administer that determined amount ofprostaglandin over the selected time period.

In use, the prostaglandin compound can be stored in unopened amplulesand may be stable for up to two years in a refrigerated condition. Whenthe prostaglandin compound is dissolved in a saline solution or glucoseto form an infusion solution, this infusion solution can be stable forup to about 24 hours.

The prostaglandin is administered to the region in which an angioplastyprocedure is to take place in an amount of about 25 nanograms to about400 nanograms and preferably about 80 nanograms to about 260 nanogramsand even more preferably in an amount of about 130 nanograms, based onprostaglandin E-1, for bolus injections. In some cases, it is desirableto intravenously administer the prostaglandin compound after theangioplasty procedure, as for example, generally continuously during a12 hour period after the procedure, and which may vary somewhere betweenabout 9 to about 15 hours. In this case, the prostaglandin compound isadministered in an amount of about 10 to about 100 nanograms perkilogram of body weight per minute after the procedure, based onprostaglandin E-1, and during the 9 to 15 hour period.

More preferably, the prostaglandin compound is intravenouslyadministered in an amount of about 15 to about 40 nanograms per kilogramof body weight per minute after the procedure, based on prostaglandinE-1, and during the 9 to 15 hour post angioplasty period. Here again,the amounts which are administered will vary from patient to patient,depending on those patient factors mentioned above, e.g. health, age,coronory health history, reaction to administration, etc.

The present invention also provides compositions which are effective forreducing dysfunction in angioplasty procedures and which involve the useof the prostaglandin compounds. The compositions generally comprise acarrier which contains a selected amount of the prostaglandin. Thecarrier must be one which does not alter the prostaglandin compound anddoes not inhibit its effectiveness. The carrier must also release theprostaglandin compound at a rate sufficient to dilate the blood vessels.Naturally, the carrier should be in a form which is capable of beingintravenously introduced.

Each of the other prostaglandin compounds which are encompassed by thepresent invention have an efficacy directly related to that ofprostaglandin E-1. Thus, the amounts of the other prostaglandincompounds which may be employed in the present invention are based uponthe efficacy of such prostaglandin compounds compared to the efficacy ofprostaglandin E-1. For this purpose, the amount of any prostaglandincompound which is used in a carrier is present in an amount necessary toproduce an efficacy approximately equivalent to the efficacy produced byat least a minimum of 25 nanograms of prostaglandin E-1 to the efficacyproduced by a maximum amount of about 400 nanograms of prostaglandinE-1.

The efficacy which is produced by any other prostaglandin compoundencompassed by the present invention can be easily related to theefficacy produced by prostaglandin E-1 based on trial techniques. Inother words, it is relatively simple to determine the efficacy producedby using, for example, prostaglandin I-2 and to determine the efficacyproduced by using prostaglandin E-1 such that the skilled artisan caneasily determine the amounts of any other prostaglandin to be used basedon the use of prostaglandin E-1. It should be understood that theefficacy which can be achieved by the prostaglandin compounds willnaturally vary from patient to patient, although the beneficial resultswhich have been achieved by use of the method and the compositions ofthe present invention are easily noticeable. Thus, the efficacy of agiven prostaglandin compound cannot be precisely determined with respectto prostaglandin E-1, but is capable of being approximately equivalentlydetermined taking into consideration the various divergences which willoccur from patient to patient.

In the case of the prostaglandin I-2 compound, this prostaglandincompound would be present in the composition administered to the patientimmediately before and immediately after the angioplasty procedure in atotal amount of about 3.7 nanograms to about 75 nanograms. Theprostaglandin I-2 more preferably would be administered in a range ofabout 12 nanograms to about 49 nanogram. The ciprostene prostaglandincompound would be present in the composition and administered to thepatient immediately before and after the angioplasty procedure in atotal amount of about 187 nanograms to about 6000 nanograms. Theciprostene prostaglandin preferably would be administered in a range ofabout 600 nanograms to about 3900 nanograms, and even more preferablyabout 1430 nanograms.

The above described quantities of prostaglandins are all based on theuse of bolus injections. The amounts specified are also based on oneintracoronary bolus injection prior to the angioplasty procedure and onebolus injection after the angioplasty procedure. Thus, each injectionwould be based on one-half the amounts specified. If intracoronaryinjections are made during the procedure, the amounts administeredbefore and after would be altered. Further, the amounts administered mayvary from patient to patient for the reasons mentioned above.

There are three general groups of carriers which have been found to behighly effective for use in the compositions of the invention. Thesecarriers include isotonic solutions as well as two forms of hypertonicsolutions. One type of hypertonic solution includes the angiographiccontrast materials and the second form of hypertonic solution includesthe biodegradable prostaglandin carrying spheres.

The isotonic solutions are generally all liquid in form and aretypically various salt solutions. One of the preferred isotonicsolutions is a saline solution present in an amount of about 5 cc. Thisamount of saline is effective to hold about 25 to about 400 nanograms ofthe prostaglandin E-1 compound. This amount of saline solution is alsoeffective for generally all of the other prostaglandins encompassed bythe present invention.

Other types of isotonic solutions which can be employed are 0.9 percentsodium chloride or some dextrose solutions, as for example a fivepercent (5%) dextrose solution. It is also possible to use a fivepercent (5%) dextrose solution with 0.2 percent sodium chloride therein.Lactated Ringers are also effective as one of the liquid carriers Theisotonic liquid carrier should have an osmolar strength about equivalentto that of seawater.

Angiographic contrast material can also be used as an effective carrierfor the prostaglandin compounds. Many of the angiographic materialswhich may be used are usually X-ray absorbent as for example,hypaque-sodium. Potassium iodine and certain other recognized potassiumsalts may also be used as the carrier solution. It is also possible touse multiple ionic materials such as potassium iodide and ironcombinations as the carrier since they all function as angiographiccontrast materials.

The amount of the angiographic contrast material which is employeddepends upon the amounts which are normally used to achieve thenecessary contrast in an angiography procedure. Usually, about 3 cc toabout 10 cc of the angiographic contrast material is used as the carrierper bolus injection.

The third group of carrier materials are the prostaglandin carryingmicrospheres. Generally, three major types of microspheres may beemployed and these include: (1) protein laden microspheres, (2)carbohydrate laden microspheres and (3) free fatty acid ladenmicrospheres.

The protein laden microspheres may include, for example, albumen ladenmicrospheres. The carbohydrate laden microspheres may include, forexample, various known and accepted starch laden microspheres as well asvarious known polysaccharides. Liposome is an effective example of a fatladen microsphere.

The term "microsphere" is used to represent particles ranging in sizefrom about 7 μ, the diameter of a red blood cell, to about 100 μ indiameter. A particular group of "uniformly" sized microspheres may varyin diameter up to around 25%. Thus, a group of 10 μ diametermicrospheres might range in size from around 8.5 μ to around 11.5 μ indiameter. Usually, about 225,000 to about 500,000 microspheres arepresent as the carrier for a bolus injection.

The microspheres of the present invention may be composed of any longchain compound susceptible to cross linking to a solid in which amide orcarboxyl groups are exposed or are capable of being exposed by suitabletreatment. This includes, but is not limited to, latex materials such aspolystyrene and styrene divinylbenzene, agarose, polyalkylcyanocrylate,albumin, cross-linked albumin, sucrose, starch, cellulose and dextran.Usually, about 225,000 to about 500,000 microspheres are present as thecarrier for a bolus injection.

As indicated previously, the prostaglandin compound may be administeredfor a selected time period, as for example, nine to 15 hours after theangioplasty procedure. This intravenous administration, when coupledwith the previously described intracoronary administration has beenfound to produce highly effective results. The amount of prostaglandinin the solution, which is administered drop-wise, should be in the rangeof about 10 nanograms to about 100 nanograms per kilogram of body weightper minute for prostaglandin E-1. Preferably, the prostaglandin E-1 isadministered in a range of about 15 to about 40 nanograms per kilogramof body weight, per minute and even more preferably about 20 nanogramsper kilogram of body weight per minute.

The amount of the other prostaglandin compounds which would beadministered intravenously is also based on the efficacy of such otherprostaglandins related directly to the efficacy of prostaglandin E-1.Thus, the prostaglandin in the carrier to be administered to a patientis present in an amount to deliver to the patient a desired weight ofprostaglandin in nanograms per kilogram of body weight of the patientper minute to produce an efficacy equivalent to the efficacy ofprostaglandin E-1 when administered in the selected range.

In a more preferred embodiment, the amount of prostaglandin E-1 isadministered in a range of about 15 nanograms to about 40 nanograms perkilogram of body weight per minute, as aforesaid. With respect to theprostaglandin I-2 compound, this prostaglandin would be administered inan amount of about 1.5 nanograms to about 19 nanograms and preferably ina range of also 2 to about 7.5 nanograms per kilogram of body weight perminute. Ciprostene would be administered in an amount of about 75nanograms to about 1500 nanograms and preferably about 112 to about 600nanograms per kilogram of body weight per minute.

It has also been found in accordance with the present invention, thatthe intraveneous administration of the prostaglandin compound followedby the intracoronary administration substantially reduces the restenosiswhich was normally encountered in angioplasty procedures. It may beobserved from the following Example III that there was a marked decreasein restenosis when the intraveneous administration of prostaglandinfollowed the intracoronary administration. In addition, when the amountof prostaglandin is reduced progressively to 0 during the last hour ortwo hours of the intravenous administration, there is a reduced tendencyfor the patient to suffer adverse effects.

The present invention is effective in providing compositions containingthe above identified amounts of prostaglandin for ready administrationof the same. Thus, and for example, a composition may contain a carrierand the amount of prostaglandin carried by that carrier which isnecessary to produce an efficacy approximately equivalent to theefficacy produced by adminstration of prostaglandin E-1 in a range ofabout 25 nanograms to about 400 nanograms. More preferably, thiscomposition would contain the prostaglandin compound necessary toproduce an efficacy in a range approximately equivalent to the efficacyproduced by the administration of 80 nanograms to about 260 nanograms ofprostaglandin E-1.

The composition also preferably includes those carriers which werementioned above and include those selected from the class consisting of(a) an isotonic solution, (b) an angiographic contrast material and (c)biodegradable prostaglandin carrying microspheres.

In another embodiment, the composition of the present invention may bedescribed as that composition which comprises the carrier for theprostaglandin compound and also the prostaglandin compound which iscarried by that carrier. The prostaglandin is present so that it canadministered over a selected time period at a relatively constant rateand in an amount to produce an efficacy approximately equivalent to thatproduced by the administration of prostaglandin E-1 in a range of about10 nanograms to about 100 nanograms per kilogram of body weight perminute. In this way, the composition thereby provides thecyto-protection and the antithrombotic effects and the antiplateleteffects and the antispasmic effects.

The present invention also provides a kit or package containing thenecessary components containing the prostaglandin compound in amounts tobe administered in the proper dosage. Thus, a kit may be initiallyprovided with a first syringe containing the amount of prostaglandincompound necessary to produce an efficacy produced by administration of12 to about 200 nanograms of prostaglandin E-1 and preferably theefficacy produced by the administration of about 40 to about 130nanograms of prostaglandin E-1. The kit would also contain a secondsyringe for a bolus injection and which would also contain aprostaglandin compound present in an amount to produce an efficacyapproximately equivalent to the efficacy of about 12 nanograms to about200 nanograms of prostaglandin E-1 and preferably an efficacyapproximately equivalent to that produced by the administration of about40 nanograms to about 130 nanograms of prostaglandin E-1. Finally, thiskit or package would also include a container such as a sealed packagecontaining the amount of prostaglandin compound necessary to provideintraveneous administration or the selected time period of 9 to about 15hours.

As a specific example of a package, the first syringe or container wouldcontain about 65 nanograms of prostaglandin E-1 in a 1 cc salinesolution and which may be diluted to about a 5 cc saline solution foruse. The kit would also include a second syringe or container whichcontains about 65 nanograms of prostaglandin E-1 in 1 cc of a salinesolution and which again may be dilluted to about a 5 cc saline solutionin use. Finally, the package or kit of the present invention wouldinclude, in this example, a container of the saline solution whichadministers about 15 to about 40 nanograms of prostaglandin E-1 perkilogram of body weight per minute for a 12 hour period.

EXAMPLES

The invention is further described by but not limited to the followingexamples.

EXAMPLE I

In order to assess the effects of intracoronary prostaglandin E-1 onmyocardial blood flow in relation to a successful coronary angioplasty,twelve patients were given sixty five nanograms of the prostaglandin E-1which was hand injected by bolus under blinded conditions. Theangioplasty procedure involved a residual luminal diameter of less than40 percent. The sixty five nanograms prostaglandin E-1 was dissolved inabout four mililiters of dehydrated alcohol. Twelve additional patientswere given four mililiters of dehydrated alcohol as a placebo andcontrol agent.

Digital radiographic assessments of contrast medium appearance timedistal to the stenosed coronary artery under hypermic conditions weremade 45 seconds after the start of the angioplasty procedure. The sameradiographic assessment was made as a control under non-hypermicconditions on an intracoronary placebo 45 seconds after the start of theangioplasty procedure. This information was used to measure myocardialblood flow immediately before and after the administration of theprostaglandin E-1. The known accepted method of the reciprocal of thecoronary flow ratio (CFR) was used to measure myocardial blood flow.Neither the prostaglandin E-1, nor the placebo elicited any angina,dysrythemia or any significant pressure changes.

This study revealed the following data in which PGE-1 is theprostaglandin E-1 compound and PTCA represents the percutaneoustransluminal coronary angioplasty procedure. N represents the number ofpatients, MBF represents the myocardial blood flow and CFR representsthe coronary flow ratio, LAD represents the left anterior descendingcoronary artery and RCA represents the right coronary artery.

    ______________________________________                                                            LAD or                                                                        RCA                                                       Parameter     N     Stenosis  CFR                                             ______________________________________                                        IC Placebo                                                                            Pre-PTCA  6     80.4 ± 11                                                                          1.02 ± 0.13]p = NS                         IC PGE-1                                                                              Pre-PTCA  6     80.4 ± 11                                                                          1.14 ± 0.17                                IC Placebo                                                                            Post-PTCA 6     24.6 ± 10                                                                          1.48 ± 0.14]p = .001                       IC PGE-1                                                                              Post-PTCA 6     24.6 ± 10                                                                          2.16 ± 0.34                                ______________________________________                                    

EXAMPLE II

In order to evaluate post angioplasty effects in which prostaglandin wasadministered, 40 patients were selected between the ages of 18 and 75.The patients were males or otherwise post-menopausal or sterilizedfemales. The patients undergoing the post transluminal coronaryangioplasty exhibited incapacitating angina or chronic stable anginawhile on maximal medical therapy.

Patient Selection and Grouping

Patients who had a cerebrovascular accident or acute myocardialinfarction within two months prior to the test were excluded. Alsoexcluded were patients having unstable ventricular arrhythemiarefractory to conventional anti-arrhythemic therapy. Also excluded wereany patients that had cancer within the past two years unless a completecure was clinically evident for two years. Patients with streptokinaseand patients with acute respiratory infections, or patients who have hadsurgery within several weeks preceeding the test were also excluded.Further excluded were patients that had pericardial infusion and/orsevere difuse pulmonary aveolar edema, patients with previousangioplasty vessel dilation, patients with coagulation disorders, activebleeding sites or gastrointestinal bleeding, or patients with poorlycontrolled diabeties mellitus.

The patients were divided into three groups which included a so-called"drug group", that is a group in which the patients were known to havereceived the prostaglandin E-1 compound, a so-called "open label" groupin which the patients received either a placebo compound or otherwisethe prostraglandin E-1 compound. The patients in this "open label" groupreceived compositions handed to the physicans properly marked by apharmacist, although the identification as to which patient in the "openlabel" group received the prostaglandin compound and which patientreceived a placebo was known only to the pharmacist and not to thephysicians. Finally, the third group or so-called "placebo" group,received only a placebo composition which included only a dehydratedethyl alcohol.

Nine patients were included in the placebo group, eight patients wereincluded in the drug group and seven patients were in the open labelgroup. The placebo group was comprised of six men and three women. Therewas one death within twenty four hours in post-angioplasty, due toabrupt occlusion. Two of the patients in the placebo group did endureprolonged angina. In the drug group, patients were of a similar agehaving an average of fifty four years and was comprised of seven men andone woman. There were not abrupt occlusions, episodes of prolongedangina or any significant complications experienced in this group.Finally, in the open label group, five of the patients were men and twowere women in a similar age range. No complications were exhibited inany patient in this post-angioplasty group.

Procedural Steps

Prior to the insertion of the balloon catheter, all of the patientsreceived 10,000 bolus units of heparin and intravenous nitroglycerine,as required, as well as subliminal nitrate and beta blockers orintraveneous verapamil.

Prostaglandin E-1 was injected at sixty five nanograms intracoronarybefore and after the angioplasty procedures. Further, twenty nanogramsper kilogram of body weight per minute were then infused into thepatients over a twelve hour period, intravenously while monitoring thepatients in an intensive care unit. The dosage was gradually tapered to0 over the last six hours of this twelve hour period. The prostaglandincomposition was infused through the ballon catheter into the myocardiumat the time of prolonged ballon inflation.

The placebo composition was administered to the patients in the placebogroup much in the same manner as the prostaglandin E-1 was administeredto the patients in the drug group. Finally, the proper composition knownby the pharmacist was administered to each of the patients in the openlabel group. In the case of those patients in the drug group, duringinflation and total occlusion, the prostaglandin composition infusionoccured intraveneously in the dosage specified.

Thereafter, a 2D echocardiogram is placed over the heart during theocclusion and an LV function change was measured simultaneously.Further, alpha platelet IV as well as beta thromboglobulin was measuredimmediately and fifteen minutes after balloon inflation.

The 2D echocardiogram was re-measured at three and six month intervalsafter the angioplasty procedure in order to determine the effects of theprostaglandin composition and the angioplasty procedure itself on leftventrical function, both globally and regionally. Also, duration ofreactive hypermia was measured after ballon inflation along with agradient as an approximation of coronary blood flow.

Method of Measuring Coronary Blood Flow

The method of Vogel, et al was used to measure coronary blood flow(Application of Digital Techniques to Selective Coronary Arteriography.Use of Myocardial Contrast Appearance to Measure Coronary Flow Reserve,American Heart Journal, Volume CVII, Number 1, January 1984).

The prostaglandin compound is used as a hyperemia inducing substance,instead of being used for contrast. Beyond that, the method andequipment are identical. Digital processing of the 35 mm. cine films wasdigitized. Gated interval differencing and functional image generationwere employed in accordance with the method of Vogel. The digital imageswere stored in a disk memory and subsequent processing was performed ona mini computer.

A single intensity and color modulated functional image is generated infive colors. Each corresponds to one of the five post-contrast orprostaglandin injection cardiac cycles analyzed and are used to displaythe cycle in which contrast medium appeared in each pixel.

In accordance with the technique described by Vogel, supra, 256intensity levels were used to depict the relative amount of the increasein contrast medium that occured in each pixel during its appearance in acycle. This form of dual-function arteriographic image has been termed"contrast medium appearance picture". This is coupled with themyocardial contrast appearance time, i.e. the time from the onset ofcontrast injection to its appearance within the region of myocardium,and this was then used as an index of regional coronary blood flow.

In order to measure intracoronary blood flow before and afterprostaglandin administration, digital radiographic assessment ofcontrast medium appearance time distal to the targeted stenosed coronaryartery was used. Measurements were made for prostaglandin P-1 underhyperemic conditions, i.e. 65 nanograms of intracoronary prostaglandinE-1 after 45 seconds, versus a control, and nonhyperemic conditions,i.e. intracoronary placebo (5 cc. of absolute alcohol), to measuremyocardial blood flow before and immediately after the coronaryangioplasty. The accepted method of the reciprocal of the coronary flowratio was used to determine myocardial blood flow, substituting,however, intracoronary prostaglandin E-1 for contrast as the hyperemiainducing agent. Neither the intracoronary prostaglandin E-1 nor placeboelicited any angina, dysrhythmia, or significant pressure changes.Equivalent dosages for other intracoronary E-1 like prostaglandins arealso employed, based on the compound's potency as compared tointracoronary prostaglandin E-1. The intravenous route is preferred forintracoronary prostaglandin E-1 like prostaglandin compounds (includingPGE-12, its salts, esters, and amids). However, other systemic routes ofadministration (e.g. oral, parenteral, intra-arterial) may also beemployed as long as the dosage used achieves the same blood level ofdrug as the intravenous route.

As summarized by Vogel in The Radiographic Assessment of Coronary BloodFlow Parameters, Circulation, Volume LXXII, Number 3, September 1985,this imaging technique to measure coronary blood flow is performedrapidly during cardiac catheterization. However, atrial pacing, ECGsynchronized power injection of contrast media, digital radiographicequipment capable of direct digital storage and fixed patientpositioning were added to the routine technique and did not result inany problems.

Results

Seventeen doubly blinded patients did provide data which allowed forcomplete analysis. Nine patients were given the placebo hand-injected,bolus, intracoronary before and after the angioplasty procedure, and themyocardial blood flow was measured as described above.

Under double blinded conditions, the placebo given was the 4 or 5 cc. ofdehydrated alcohol, and this same vehicle was used for the prostaglandinE-1. In this group of nine, there was one death in 24 hours and twoepisodes of prolonged angina documented by ECG change. This did notappear in the patients given the 65 nanograms of intracoronaryprostaglandin E-1 hand-injected, bolus, in the doubly blinded druggroup.

The percent stenosis of the target vessel in the placebo and drug groupswere similar, being 80 percent mean pre-angioplasty and 25 percent meanpost-angioplasty, as measured by standard visual criteria. The patientsreceiving the drug in the open label group had similar degrees ofstenosis in their coronary arteries prior to angioplasty. The incidenceof unstable angina, antecedent myocardial infarction, or post-infarctionangina, was similar in all three groups, namely, 33 percent in theplacebo group, 25 percent in the drug group, and 29 percent in the openlabel group, regarding myocardial infarction, one patient with unstableangina post-infarction in the drug group, none in the placebo group, andtwo in the open label group.

When comparing the placebo group with the intracoronary drug group, thenine patients receiving the intracoronary placebo injection,pre-coronary angioplasty, showed a reciprocal of the coronary flow ratioof 1.04±0.13 standard error of the mean Eight patients in the druggroup, pre-coronary angioplasty, and the seven patients in the openlabel group, pre-coronary angioplasty, showed a coronary flow ratio of11±0.17, and the difference between the placebo and drug group was notsignificant pre-angioplasty. It should be noted that despite the tightflow limiting stenoses in the ascending coronary arteries, intracoronaryprostaglandin E-1 did augment flow slightly, but this was notsignificant because of the flow limiting stenosis.

The nine patients in the placebo group, post-angioplasty, had a coronaryflow ratio of 1.54±0.12, which is higher than the pre-coronaryangioplasty flow. In the drug group and the open label group, thecoronary angioplasty elicited an intense hyperemia, which yielded acoronary flow value of 2.31±0.34 with the P-value of points less than0.001 using a student two tailed T-test. In the open label group, theduration of the hyperemia was tested with two and five minuterepetitions of the coronary flow value and the hyperemia was still muchabove a baseline flow. In two patients in the open label group, thecomparison of the hyperemic response of intracoronary prostaglandin E-1was 22 percent higher than judged by the coronary flow value.

Two-dimensional echocardiography was performed immediately after theangioplasty and repeated at least once within two days prior to thepatient being discharged, i.e. whenever clinically feasible. Theechocardiography did show, in the placebo group, no significant increasein regional ventricular function. In the doubly blinded drug group,three of eight patients did show increase in regional function as judgedby independent analysis by a blinded investigator, via 2Dechocardiographic criteria. In the open label group, two of sevenpatients did show dramatic increase in regional LV function. However,one patient did have unstable angina prior to the angioplasty.

Conclusions

Based on the foregoing analysis, it was concluded that the intracoronaryprostaglandin E-1 and the intravenous prostaglandin E-1 in the abovedescribed dosages was safe and created no serious side effects.Moreover, the prostaglandin compounds, when used as described herein,elicit an intense hyperemia, at least doubling coronary blood flowdirectly. This effect appears to be prolonged without inducing anyhemodynamic complications, such as hypotension.

The vasodilating and hyperemic effects of prostaglandin E-1 appear to bea direct result of its antispasm effect in the area where the plaque isruptured by balloon dilation. Angiography reveals that there appears tobe, in almost all instances of angioplasty, a subintimal disruption andwhich is the technique by which the plaque is fractured during theangioplasty procedure and hence the flow obstruction removed.

Thus, it was concluded that in unstable angina the prostaglandin E-1 andthe other prostaglandin compounds do inhibit platelet aggregation at thesite of antheroma fracturing during angioplasty. Consequently,embolization of microemboli platelets in a downstream position is notnoted. As a result, and as could be anticipated, prolonged angina orabrupt closure was not observed in the drug group, as it was observed inthe placebo group.

It was postulated that it is really impossible to determine theappearance and condition of coronary vessels in a post-angioplastyprocedure by angiographic criteria. Under pathologic studies previouslyperformed, and under angioscopy, a roughing and tearing of the intimaand media is almost always observed. Consequently, the angiogramtherefore underestimates the amount of damage to a vessel which issubjected to an angioplasty procedure. The site of the procedure isunable to synthesize local prostaglandins. Thus, the thromboxane that isreleased by the platelets is unopposed which results in spasm orthrombus. The exogenous prostaglandin E-1 and the other prostaglandincompounds encompassed by the present invention delivered in sufficientdosages in accordance with the present invention clearly overcomes theseeffects.

It was also concluded that the hyperemic or increased blood flow stateinduced by the intracoronary prostaglandin was prolonged more than withintravenous nitroglycerine. Thus, it was also concluded that it isdesirable, in most cases, to continue the intravenous prostaglandin E-1for at least 12 hours post-angioplasty and post-intracoronary injectionto obtain the most beneficial effects of the prostaglandin compound.

Based on the foregoing, it was concluded that the prostaglandin compoundexhibits substantial antithrombotic and antiplatelet effects, as abruptocclusion and thrombosis were not observed in the drug group, but wereobserved in the placebo group. The prostaglandin compound does exhibit amyosite protection effect, both cellular and as an inhibitor of plateletaggregation.

EXAMPLE III

Forty patients were evaluated in a double blind study in order todetermine whether an intravenous infusion of prostaglandin E-1 producedthe desired salutary effects after a coronary angioplasty prodcedure.Twenty to forty nanograms per kilogram per minute of prostaglandin E-1(test patients) versus a normal saline placebo (placebo patients) wereinfused into certain of the test patients for a period of twelve hoursafter the angioplasty procedure. Further, one hundred and thirtynanograms bolus of prostoglandin E-1 was administered in anintracoronary procedure during the angioplasty procedure. All of thepatients were prepared prior to angioplasty in accordance with thetypical procedures with asprin, dipyridamole, heparin, nitrites andnifedipine and/or verapamil. Moreover, administration of these latterdrugs continued after the angioplasty procedure.

The prostaglandin E-1 produced a reduction in a number of eposides ofabrupt occulsions with three occuring in eighteen patients which did notrecieve the prostaglandin E-1 and none in fourteen patients which didreceive the prostaglandin E-1. All patients with disection and/or longspasm had repeat angiograms within seven days. With disection during theangioplasty procedure, prostaglandin E-1 inhibited prolonged spasms (2/5for those patients not receiving the prostaglandin and 0/6 for thosepatients receiving the prostaglandin) and restenosis despite systemicheparinization for two to seven days after the angioplasty procedure(2/2 for patients not receiving the prostaglandin E-1 versus 0/6 forpatients receiving the prostaglandin E-1).

Adverse effects of prostaglandin E-1 infusion at this stage did notoccur, primarily because the patients were deliberately volumeoverloaded. In conclusion, it was determined that a prostaglandin E-1injection intracoronary followed by intravenous infusion in patientsundergoing the angioplasty procedure is quite safe. Prostaglandin E-1appears to inhibit coronary spasms and abrupt occulsion, particularlywhen disection is produced by the angioplasty procedure. This salutaryclinical effect of prostaglandin E-1 occurs in addition to the effectsof standard pharmaceutical agents currently used in angioplastyprocedures.

One of the unique results which has been found in connection with thepresent invention is a very substantial reduction in restenosis, as isevident by the foregoing Example III. The problem of restenosis inconnection with angioplasty procedure is one which has plaguedcardiologists for a long period of time. Moreover, little is known aboutthe causes of restenosis. Nevertheless, it has been observed that thereis a very substantial decrease in restenosis when the prostaglandincompound is administered in the ranges described herein.

More specifically, it has been found that the restenosis is decreasedsubstantially as a result of the intra-arterial administrationimmediately before and/or immediately after the angioplasty procedureand which is followed by the intravenous administration of theprostaglandin, as described above. In the forty cases tested, as inExample III, only five of the patients demonstrated early restenosis andall five patients were in the placebo group. In other words, allpatients who received the prostaglandin compound in accordance with theprocedure specified herein suffered no early restenosis. It is preferredto use the same prostaglandin compound for the intravenousadministration as was used for the intra-arterial administration,although this is not absolutely necessary.

Although it is not certain, it is theorized that the post-angioplastyprocedure intravenous infusion in combination with the intracoronaryadministration leads to the significant results and substantialreduction of restenosis. It is believed that the infusion during thelast nine to fifteen hours and preferably the last twelve hours affectsthe platelet deposition and platelet aggregation. Thus, by reducing theplatelet deposition and aggregation, previously encountered problems ofearly restenosis have been reduced, if not fully eliminated.

It will be appreciated therefor, from the foregoing description, thatthe present invention represents a significant advance in the reductionof dysfunction resulting from angioplasty procedures and particularlyfrom myocardial angioplasty procedures. In particular, the inventionprovides for the method of administering a prostaglandin compound in adesired amount in order to provide cyto protection and to provideantithrombotic effects, antiplatelet effects and antispasmic effects. Ingeneral, the prostaglandin, when administered in the proper amounts,also aids in the dilation of the artery. Although the invention has beendescribed in relation to a specific embodiment for purposes ofillustration, it should be understood that various modifications may bemade without departing from the spirit and scope of the invention.Accordingly, the invention is not to be limited, except as by theappended claims.

Having thus described our invention, what we desire to claim and secureby letters patent is:
 1. A method for preventing or treating arterialdysfunction resulting from angioplasty procedures in an artery of humanbeings, said method comprising: initially introducing into said arteryprostaglandin E₁ or a prostaglandin pharmacologically equivalentthereto, in an amount of at least 25 nanograms prior to beginning saidprocedure and then continuing to introduce into the artery theprostaglandin compound during said procedure.
 2. The method of claim 1wherein said artery is a myocardial artery or coronary artery.
 3. Themethod of claim 1 wherein said prostaglandin compound is introduced inan amount to produce an efficacy approximately equivalent to thatproduced by the administration of about 80 nanograms to about 260nanograms of prostaglandin E-1.
 4. The method of claim 1 wherein saidprostaglandin compound is additionally administered by intravenous meansfor a period ending about 9 hours to about 15 hours after saidangioplasty procedure.
 5. The method of claim 4 wherein said intravenousadministration occurs during a period ending about 12 hours after saidangioplasty procedure.
 6. The method of claim 4 wherein the amount ofprostaglandin compound administered intraveneously is calculated on thebasis of an amount per kilogram of body weight to produce the efficacyproduced by the intravenous administration of about 10 to about 100nanograms per kilogram of body weight per minute of prostaglandin E-1.7. The method of claim 6 wherein the amount of prostaglandin compound iscalculated on the basis of an amount per kilogram of body weight toproduce the efficacy produced by the intravenous administration of about15 to about 40 nanograms per kilogram of body weight per minute ofprostaglandin E-1.
 8. The method of claim 1 wherein said prostaglandincompound is selected from the group consisting of prostaglandin E-1,prostaglandin I-2 and ciprostene.
 9. The method of claim 8 wherein saidprostaglandin compound is prostaglandin E-1.